WO2006119329A2 - Compositions et procedes pour traiter des maladies neurodegeneratives - Google Patents

Compositions et procedes pour traiter des maladies neurodegeneratives Download PDF

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WO2006119329A2
WO2006119329A2 PCT/US2006/016905 US2006016905W WO2006119329A2 WO 2006119329 A2 WO2006119329 A2 WO 2006119329A2 US 2006016905 W US2006016905 W US 2006016905W WO 2006119329 A2 WO2006119329 A2 WO 2006119329A2
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agents
agent
neurodegenerative disease
patient
administered
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WO2006119329A3 (fr
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Jane Staunton
Xiaowei Jin
Dina Solimini Rufo
Michael Monteiro
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Combinatorx, Incorporated
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/365—Lactones
    • A61K31/375—Ascorbic acid, i.e. vitamin C; Salts thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca

Definitions

  • SMA Proximal Spinal Muscular Atrophy
  • SMA Proximal Spinal Muscular Atrophy
  • SMA is an autosomal recessive disorder in which alpha motor neuron death in the spinal cord is observed.
  • the primary genetic lesion that causes SMA is a deletion or mutation of the telomeric copy of the survival motor neuron gene (SMNl).
  • SSN2 survival motor neuron gene
  • SMA2 centromeric survival motor neuron gene
  • This information has lead to the generation of a mouse model of SMA, in which the single mouse SMN gene is deleted and the resulting embryonic lethality is suppressed by introduction of the human SMN2 transgene.
  • SMN is a 38 kDa protein ubiquitously expressed in both cytoplasm and nuclei. In the nucleus, SMN is found in gemini of coiled bodies (gems), named for their association with coiled bodies. SMN associates with itself and forms a complex with a series of proteins, including the Sm proteins, SIP-I (gemin 2), gemin 3 and gemin 4 and possibly other proteins. This SMN-containing complex functions in snRNP biogenesis, participating in pre-mRNA splicing in the nucleus. A series of other proteins have been reported to interact with SMN, including profilins, E2 and FUSE, suggesting other possible roles for SMN.
  • SMN protein levels This deficiency results in the selective degeneration of lower motor neurons and the loss of motor function, and is frequently fatal.
  • Small molecules that increase the amount of SMN protein in cells are much sought after for their potential therapeutic value to SMA patients.
  • Previous screens and research efforts have been directed towards discovering small molecules that alter splicing of the SMN2 pre-mRNA, or of compounds that activate the SMN2 promoter.
  • many of these compounds do not increase the amount of SMN protein in cells by a significant amount.
  • most of the identified compounds show toxicities that limit their therapeutic suitability.
  • the invention features a composition that includes: (a) a first agent selected from the agents of Table 1; and (b) a second agent useful for treating a neurodegenerative disease.
  • the first agent and the second agent are present in amounts that, when administered to a patient, are sufficient to treat a neurodegenerative disease or increase SMN protein levels (i.e., result in a statistically significant increase in SMN protein levels compared to a control).
  • the composition optionally includes one or more additional agents selected from Table 1.
  • the composition may be formulated for oral or systemic administration.
  • the two agents are ascorbic acid and memantine; ascorbic acid and indoprofen; ascorbic acid and amantadine; ascorbic acid and guanfacine; ubenimex and amantadine; amrinone and memantine; amrinone and amantadine; amrinone and indoprofen; amrinone and guanfacine; guanfacine and memantine; gunafacine and amantadine; alosetron and memantine; alosetron and amantadine; or indoprofen and memantine.
  • the invention also features a method for treating a neurodegenerative disease or increasing SMN protein levels in a patient having SMA by administering to a patient in need thereof one, two, or more agents selected from the agents of Table 1 in an amount sufficient to treat the neurodegenerative disease or increase SMN protein levels. Iftwo or more agents are administered, it is desirable that the agents be administered simultaneously or within 28 days, 14 days, 10, days, 7 days, or 24 hour of each other, or simultaneously, in amounts that together are sufficient to treat the neurodegenerative disease or increase SMN protein levels.
  • the two agents are ascorbic acid and memantine; ascorbic acid and indoprofen; ascorbic acid and amantadine; ascorbic acid and guanfacine; ubenimex and amantadine; amrinone and memantine; amrinone and amantadine; amrinone and indoprofen; amrinone and guanfacine; guanfacine and memantine; gunafacine and amantadine; alosetron and memantine; alosetron and amantadine; or indoprofen and memantine.
  • the method may further include the step of administering to the patient one or more additional therapeutic agent useful for treating a neurodegenerative disease, such as those described herein.
  • the different agents may be admixed together in a single formulation.
  • the agents may be administered simultaneously or within 14 days, 7 days, or 1 day of each other. These agents may or may not be administered by the same route of administration (e.g., oral, intravenous, intramuscular, ophthalmic, topical, dermal, subcutaneous, and rectal). If desired, an agent maybe administered at a high dosage, low dosage.
  • kits for treating neurodegenerative diseases include (i) an agent selected from the agents of Table 1; and (ii) instructions for administering the agent to a patient having a neurodegenerative disease.
  • the kit includes (i) a composition containing two agents selected from the agents of Table 1; and (ii) instructions for administering the composition to a patient having a neurodegenerative disease.
  • kits includes (i) a first agent selected from the agents of Table 1; (ii) a second agent selected from the agents of Table 1; and (iii) instructions for administering the first and second agents to a patient having a neurodegenerative disease.
  • Still another kit includes (i) an agent selected from the agents of Table 1 ; and (ii) instructions for administering the agent with a second agent selected from the agents of Table 1 to a patient having a neurodegenerative disease.
  • kits of the invention includes (i) a composition containing (a) a first agent selected from the agents of Table 1 ; and (b) a second agent that is useful for treating a neurodegenerative disease; and (ii) instructions for administering the composition to a patient having a neurodegenerative disease.
  • a composition containing (a) a first agent selected from the agents of Table 1 ; and (b) a second agent that is useful for treating a neurodegenerative disease; and (ii) instructions for administering the composition to a patient having a neurodegenerative disease.
  • Still another kit of the invention includes (i) an agent selected from the agents of Table 1; and (ii) instructions for administering the agent and a second agent to a patient having a neurodegenerative disease, wherein the second agent is useful for treating a neurodegenerative disease.
  • kits includes (i) an agent that is useful for treating a neurodegenerative disease; and (ii) instructions for administering this agent with an agent selected from the agents of Table 1 to a patient having a neurodegenerative disease.
  • compositions, methods, and kits of the invention may be used to treat any neurodegenerative disease, including spinal muscular atrophy (SMA), spinal and bulbar muscular atrophy (SBMA), amyolateral sclerosis (ALS), Alzheimer's disease, Parkinson's diseases, and Huntington's disease.
  • SMA spinal muscular atrophy
  • SBMA spinal and bulbar muscular atrophy
  • ALS amyolateral sclerosis
  • Alzheimer's disease Parkinson's diseases
  • Huntington's disease Huntington's disease.
  • the invention also features a method of identifying a combination that may be useful for the treatment of a neurodegenerative disease.
  • This method includes the steps of: (a) contacting SMN-expressing cells with a combination comprising an agent selected from the agents of Table 1 and a candidate compound; and (b) determining whether the combination of the agent and the candidate compound increase the amount of SMN protein relative to cells contacted with the agent but not contacted with the candidate compound, wherein an increasing in the amount of SMN protein identifies the combination as a combination useful for the treatment of a neurodegenerative disease.
  • the cells are mammalian cells (e.g., human fibroblasts from an SMA patient)
  • compositions, methods, and kits of the invention may be used to treat any neurodegenerative disease, including spinal muscular atrophy (SMA), spinal and bulbar muscular atrophy (SBMA), amyolateral sclerosis (ALS), Alzheimer's disease, Parkinson's diseases, and Huntington's disease.
  • SMA spinal muscular atrophy
  • SBMA spinal and bulbar muscular atrophy
  • ALS amyolateral sclerosis
  • Alzheimer's disease Parkinson's diseases
  • Huntington's disease Huntington's disease.
  • patient any animal (e.g., a human).
  • Other animals that can be treated using the methods, compositions, and kits of the invention include horses, dogs, cats, pigs, goats, rabbits, hamsters, monkeys, guinea pigs, rats, mice, lizards, snakes, sheep, cattle, fish, and birds.
  • an amount sufficient is meant the amount of a compound, alone or in combination with another therapeutic regimen, required to treat, prevent, or reduce a metabolic disorder such as diabetes in a clinically relevant manner.
  • a sufficient amount of an active compound used to practice the present invention for therapeutic treatment of conditions caused by or contributing to diabetes varies depending upon the manner of administration, the age, body weight, and general health of the mammal or patient.
  • an effective amount may be an amount of compound in the combination of the invention that is safe and efficacious in the treatment of a patient having a metabolic disorder such as diabetes over each agent alone as determined and approved by a regulatory authority (such as the U.S. Food and Drug Administration).
  • a treatment exhibits greater efficacy, or is less toxic, safer, more convenient, or less expensive than another treatment with which it is being compared. Efficacy may be measured by a skilled practitioner using any standard method that is appropriate for a given indication.
  • a “low dosage” is meant at least 5% less (e.g., at least 10%, 20%,
  • a low dosage of an agent that reduces glucose levels and that is formulated for administration by inhalation will differ from a low dosage of the same agent formulated for oral administration.
  • a “high dosage” is meant at least 5% (e.g., at least 10%, 20%, 50%,
  • Candidate compounds may include, for example, peptides, polypeptides, synthetic organic molecules, naturally occurring organic molecules, nucleic acid molecules, peptide nucleic acid molecules, and components and derivatives thereof.
  • Compounds useful in the invention include those described herein in any of their pharmaceutically acceptable forms, including isomers such as diastereomers and enantiomers, salts, esters, solvates, and polymorphs thereof, as well as racemic mixtures and pure isomers of the compounds described herein.
  • FIGS. IA and IB are graphs showing SMN protein levels in patient (GM03813) versus carrier fibroblast cells (GM03814). Fibroblast cell lines were analyzed by SMN cytoblot, using anti-SMN antibody from BD Biosciences (FIG. IA). A scatter plot of the data used is also shown (FIG. IB).
  • FIG. 2 is a series of illustrations depicting absolute SMN fold induction of various drug combinations.
  • SMN fold induction was calculated as SMN(T- B)/SMN(U-B) where "T” is the signal from treated cells, "B” is plate-specific background, and "U” is the signal from untreated cells.
  • FIG. 3 is a series of illustrations depicting viability-controlled fold induction of various drug combinations. Viability-controlled fold induction was calculated as (SMN fold induction)/(ATP fold induction), where ATP fold induction is calculated in the same manner as SMN fold induction, or: ATP(T- B)/ATP(U-B).
  • agents that increase SMN protein levels in SMA fibroblasts in vitro may be used to increase SMN protein levels in patients having a neurodegenerative disease (e.g., SMA 5 SBMA, ALS, Alzheimer's disease, Parkinson's disease, or Huntington's disease), and may further be used to treat these patients.
  • a neurodegenerative disease e.g., SMA 5 SBMA, ALS, Alzheimer's disease, Parkinson's disease, or Huntington's disease
  • guanidinium-containing compounds such as guanfacine, guanethidine, creatine, guamecycline, guanabenz, guanadrel, guanoxabenz, and guanoxan.
  • Guanfacine N-aminoiminomethyl-2,6-dichlorobenzeneacetamide
  • Guanethidine ([2- (hexahydro-l(2H)-azocinyl)ethyl]guanidine) is an anti-hypertensive norepinephrine-depleting agent. It's chemical structure and methods of making it are described in U.S. Patent No. 2,928,829. Analogs of any of the foregoing can also be used in the compositions, methods, and kits of the invention. Such analogs are described in U.S. Patent Nos. 2,928,829; 3,247,221; 3,547,951 ; 3,591,636; 3,632,645; GB 1019120; and GB 1042207, each of which is hereby incorporated by reference.
  • transition metal salts such as manganese salts, ferric and ferrous salts, and cupric salts.
  • Exemplary transition metal salts are manganese sulfate, ferric ammonium citrate, ferrous sulfate, cupric sulfate, cupric chloride, and copper bis-3,5-diisopropylsalicylate.
  • Each of these transition metal salts acts as an antioxidant and free radical scavenger.
  • Other antioxidants and free radical scavengers may be used in the compositions, methods, and kits of the invention.
  • Analogs of any of the compounds listed in Table 1 may be used in any of the methods, kits, and compositions of the invention. Analogs are known in the art (e.g., as described herein). Altretamine analogs are described in U.S. Patent No. 3,424,752; alosetron analogs are described in U.S. Patent no. 5,360,800; amikacin analogs are described in U.S. Patent No. 3,781,268; amrinone analogs are described in U.S. Patent Nos. 4,004,012 and 4,072,746; anisotropine methylbromide analogs are described in U.S. Patent No. 2,962,499; azlocillin analogs are described in U.S. Patent No.
  • Patent No. 4,024,175 gadoteridol analogs are described in U.S. Patent No. 4,885,365; gallamine triethiodide analogs are described in U.S. Patent No. 2,544,076; gentamicin analogs are described in U.S. Patent Nos. 3,091,572 and 3,136,704; guanethidine analogs are described in U.S. Patent No.2,928,829; guanfacine analogs are described in U.S. Patent No. 3,632,645; levetiracetam analogs are described in U.S. Patent No. 4,943,639; loxapine analogs are described in U.S. Patent No.
  • paromomycin analogs are described in U.S. Patent No. 2,916,876; pazufloxacin analogs are described in U.S. Patent No. 4,990,508; pentagastrin analogs are described in U.S. Patent No. 3,896,103; pergolide analogs are described in U.S. Patent No. 4,166,182; pyrantel analogs are described in U.S. Patent No. 3,502,661; pyridostigmine bromide analogs are described in U.S. Patent No. 2,572,579; rescinnamine analogs are described in U.S. Patent Nos.
  • sirtinol ((2-[(2-hydroxy-naphthalen- 1 -ylmethylene)- amino] -N- (1-phenyl-ethy- l)-benzamide))analogs include (8,9-dihydroxy-6H- (l)benzofuro[3,2-c]chromen-6-one), M15 (l-[(4-methoxy-2-nitro- phenylimino)-methyl]-naphthalene-2-ol), butyrates (including sodium butyrate and sodium phenylbutyrate), tributytrin, trichostatin A (TSA), TPX-HA analog (CHAP compounds built from TSA and cyclic tripeptides, hydroxamic acid based), trapoxin, MS-275 (MS-27-275), NSC-706995, NSC-625748, NSC- 656243, NSC- 144168, psammaplin analogues
  • Patent Nos. 3,206,360, 3,234,092, and 3,272,706 tegafur analogs are described in Great Britain Patent No. 1168391; teicoplanin analogs are described in U.S. Patent No. 4,239,751 and 4,542,018; tiapride analogs are described in Great Britain Patent No. 1394563; ubenimex analogs are described in U.S. Patent Nos. 4,029,547 and 4,052,449; and vincamine analogs are described in U.S. Patent No. 3,770,724.
  • therapeutic agents may be administered with the agent or agents described herein at concentrations known to be effective or under investigational study for such therapeutic agents.
  • Agents useful to treat a neurodegenerative disease include the following: compounds that correct aberrant SMN protein splicing or protein levels; calcium antagonists such as nimodipine; sodium channel blockers such as fosphenytoin, sipatrigine, and lubeluzole; caspase inhibitors such as p35, ZVAD, and crniA; neuroimmunophilins; amino acids such as taurine and adenosine and other adenosine-based neuroprotectants; competitive and noncompetitive glutamate antagonists such as phencyclidine, ketamine, dizocilpine, dextromethorphan, magnesium, selfotel, MDL 104,653 (3-phenyl-4-hydroxy-7-chloroquinolin- 2(lH)-one) and gavestinel;
  • protein-based therapeutics such as RJ-820; agents that stabilize the neuronal membrane potential; neurosteroids such as allopregnanolone and dehydroepiandrosterone; anti-inflammatory or analgesic agents such as non-steroidal anti-inflammatory agents; tetracycline compounds such as minocycline; neuropeptides such as neuropeptides (opioid peptides, thyreoliberine, neuropeptide Y, galanin, VIP/PACAP, hormones such as estrogen and progestin, and caffeine); Co-enzyme QlO; creatinine; hydroxyurea; sodium or phenyl butyrate or other butyrate compounds; HDAC inhibitors such as valproate or valproic acid; aclarubicin; gabapentin; albuterol; quinazolines; aminogylcosides; and salbutamol.
  • neurosteroids such as allopregnanolone and dehydroepiandrosterone
  • agents useful to treat a neurodegenerative disease are (-)- e ⁇ igallocatechin-3-gallate; (R)-Q-BPAP; 106362-32-7; remacemide; selegiline; 4-Cl-kynurenine; A-134974; A-366833; A-35380; A-72055; ABS- 205; AC- 184897; AC-90222; ACEA- 1021 (licostinel); ADCI; AEG-3482; AGY-110; AGY-207; AK-275 (vasolex); alaptid; ALE-0540; AM-36; annovis; ampakines; amyloid-inhibiting peptides; AN- 1792; andrographolide; APBPI- 124; apoptosin; aptiganel; AR-139525; AR-15896 (lanicemine); AR-A- 008055; donepezil; AR-R-17779; AR-Rl 8565; ARRY-14
  • therapeutic agents may be delivered separately or may be admixed into a single formulation.
  • routes of administration may be employed.
  • Routes of administration for the various embodiments include, but are not limited to, topical, transdermal, and systemic administration (such as, intravenous, intramuscular, intrathecal, subcutaneous, inhalation, rectal, buccal, vaginal, intraperitoneal, intraarticular, ophthalmic or oral administration).
  • systemic administration refers to all nondermal routes of administration, and specifically excludes topical and transdermal routes of administration.
  • the agent of the invention and additional therapeutic agents are administered within at least 1, 2, 4, 6, 10, 12, 18, 24 hours, 3 days, 7 days, or 14 days apart.
  • the dosage and frequency of administration of each component of the combination can be controlled independently.
  • one compound may be administered three times per day, while the second compound may be administered once per day.
  • Combination therapy may be given in on-and-off cycles that include rest periods so that the patient's body has a chance to recover from any as yet unforeseen side effects.
  • the compounds may also be formulated together such that one administration delivers both compounds.
  • any of the agents of the combination may be administered in a low dosage or in a high dosage, each of which is defined herein.
  • the therapeutic agents of the invention may be admixed with additional active or inert ingredients, e.g., in conventional pharmaceutically acceptable carriers.
  • a pharmaceutical carrier can be any compatible, non-toxic substance suitable for the administration of the compositions of the present invention to a mammal.
  • Pharmaceutically acceptable carriers include, for example, water, saline, buffers and other compounds described for example in the Merck Index, Merck & Co., Rahway, New Jersey. Slow release formulation or a slow release apparatus may be also be used for continuous administration.
  • kits that contain, e.g., two pills, a pill and a powder, a suppository and a liquid in a vial, two topical creams, etc.
  • the kit can include optional components that aid in the administration of the unit dose to patients, such as vials for reconstituting powder forms, syringes for injection, customized IV delivery systems, inhalers, etc.
  • the unit dose kit can contain instructions for preparation and administration of the compositions.
  • the kit may be manufactured as a single use unit dose for one patient, multiple uses for a particular patient (at a constant dose or in which the individual compounds may vary in potency as therapy progresses); or the kit may contain multiple doses suitable for administration to multiple patients ("bulk packaging").
  • the kit components may be assembled in cartons, blister packs, bottles, tubes, and the like. Dosages
  • the dosage of any of the agents of the combination of the invention will depend on the nature of the agent, and can readily be determined by one skilled in the art. Typically, such dosage is normally about 0.001 mg to 2000 mg per day, desirably about 1 mg to 1000 mg per day, and more desirably about 5 mg to 500 mg per day. Dosages up to 200 mg per day may be necessary. Administration of each agent in the combination can, independently, be one to four times daily for one day to one year, and may even be for the life of the patient. Chronic, long-term administration will be indicated in many cases .
  • the compounds of the invention may be employed in mechanistic assays to determine whether other combinations, or single agents, are as effective as the combination in treating neurodegenerative diseases (e.g., SMA) using assays generally known in the art, examples of which are described herein.
  • candidate compounds may be tested, alone or in combination (e.g., with an agent that is useful for treating a neurodegenerative disease, such as those described herein) and applied to fibroblasts derived from patients diagnosed as having SMA. After a suitable time, these cells are examined for SMN protein levels. An increase in SMN protein levels identifies a candidate compound or combination of agents as an effective agent to treat a neurodegenerative disease.
  • the agents of the invention are also useful tools in elucidating mechanistic information about the biological pathways involved in SMN protein regulation. Such information can lead to the development of new combinations or single agents for treating SMA or another neurodegenerative disease.
  • Methods known in the art to determine biological pathways can be used to determine the pathway, or network of pathways affected by contacting cells (e.g., fibroblasts or motorneurons) with the compounds of the invention. Such methods can include, analyzing cellular constituents that are expressed or repressed after contact with the compounds of the invention as compared to untreated, positive or negative control compounds, and/or new single agents and combinations, or analyzing some other activity of the cell such as enzyme activity.
  • Cellular components analyzed can include gene transcripts, and protein expression.
  • Suitable methods can include standard biochemistry techniques, radiolabeling the compounds of the invention (e.g., 14 C or 3 H labeling), and observing the compounds binding to proteins, e.g. using 2D gels, gene expression profiling. Once identified, such compounds can be used in in vivo models (e.g., a mouse model for SMA) to further validate the tool or develop new agents or strategies to treat neurodegenerative diseases.
  • in vivo models e.g., a mouse model for SMA
  • the agents listed in Table 1 may act by increasing transcription, modifying splicing, inducing translational read-through, and/or increasing protein stability, and thus may, alone or in combination, be useful for treating other diseases that are caused by low expression of a gene.
  • diseases include cancers that can be sent into growth arrest by the up-regulation of tumor suppressor genes such as p53 and transcriptional targets of the retinoblastoma protein.
  • Other diseases that may be treating by administration of one or more agents listed in Table 1 include diseases caused by low gene expression due to premature stop codons, such as Duchenne muscular dystrophy and cystic fibrosis.
  • Diseases that arise from splicing defects include familial isolated growth hormone deficiency, type II (IGHD II), Frasier syndrome and other disorders that result from abnormal expression of the Wilms tumor suppressor gene (WTl), frontotemporal dementia and Parkinsonism linked to chromosome 17 (FTDP- 17), Hutchinson-Gilford progeria syndrome (HGPS), myotonic dystrophy, retinitis pigmentosa, atypical cystic fibrosis, neurofibromatosis type I (NFl), Fanconi's anemia, and breast cancer susceptibility at the BRCA1/BRCA2 loci.
  • Diseases that may benefit to therapies that increase protein stability include hematological malignancies and solid tumors, stroke, and ischemia.
  • Small molecule stimulators of SMN protein There are a variety of mechanisms that could lead to increases in SMN protein concentration; such mechanisms include transcription initiation and elongation, pre-mRNA splicing, mRNA decay and stability, translation initiation and elongation, and protein degradation. All of these mechanisms can be surveyed simultaneously by screening for small molecules that increase the amount of SMN protein in SMA patient fibroblasts. Subsequent to identifying compounds with this property, it will be possible to identify which of these specific mechanisms is responsible for each compound's effect.
  • SMA survival motor neuron
  • SMN protein levels in cells is through use of a cytoblot assay, in which cells are fixed and probed with an antibody against a target protein of interest.
  • a cytoblot assay to determine the concentration of SMN protein in SMA patient fibroblasts, and have identified small molecules that increase SMN protein concentration.
  • the two agents are ascorbic acid and memantine; ascorbic acid and indoprofen; ascorbic acid and amantadine; ascorbic acid and guanfacine; ubenimex and amantadine; amrinone and memantine; amrinone and amantadine; amrinone and indoprofen; amrinone and guanfacine; guanfacine and memantine; gunafacine and amantadine; alosetron and memantine; alosetron and amantadine; and indoprofen and memantine.
  • the results are shown in FIGS. 2 and 3.
  • Day 4 ATP lite 1-step Addition Reconstitute powder with assay buffer according to product instructions. Using PlateMate, add 50 ⁇ l per well to appropriate assay plates. Protect plates from light for ten minutes and place plates on orbital plate shaker (at least 700 RPM) for two minutes. Read plates on Wallac readers using SMAFJLumi protocol. Cell Fixation and Primary Antibody Addition: Remove remaining plates from incubator. Wash plates 2x using Tecan Plate washer with PBS, 0.1% Tween 20. Using PlateMate, add cold methanol (stored in -2O 0 C freezer) to plates, 30 ⁇ l/well. Incubate plates in 4 0 C refrigerator for ten minutes. Repeat 2X washing using Tecans. Using PlateMate, add anti-SMN or antibody to plates, 40 ⁇ l/well. Seal plates and incubate at room temperature overnight.
  • SMN fold induction was calculated as SMN(T-B)/SMN(U-B) where "T" is the signal from treated cells, "B” is plate-specific background, and "U” is the signal from untreated cells.
  • Viability controlled fold induction was calculated as (SMN fold induction)/(ATP fold induction), where ATP fold induction is calculated in the same manner as SMN fold induction, or: ATP(T-B)/ ATP(U- B).
  • HSA single agent
  • ADD Loewe additivity

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  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

La présente invention concerne des compositions et des procédés pour traiter des maladies neurodégénératives.
PCT/US2006/016905 2005-05-02 2006-05-02 Compositions et procedes pour traiter des maladies neurodegeneratives WO2006119329A2 (fr)

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US67702205P 2005-05-02 2005-05-02
US60/677,022 2005-05-02
US69818405P 2005-07-11 2005-07-11
US60/698,184 2005-07-11
US76157306P 2006-01-24 2006-01-24
US60/761,573 2006-01-24

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JP2010523684A (ja) * 2007-04-12 2010-07-15 パラテック ファーマシューティカルズ インコーポレイテッド テトラサイクリン化合物を用いる、脊髄筋委縮症を治療するための方法
US20130131006A1 (en) * 2010-05-11 2013-05-23 Gachon University Of Industry-Academic Cooperation Foundation Method for inhibiting the induction of cell death by inhibiting the synthesis or secretion of age-albumin in cells of the mononuclear phagocyte system
JP2014530810A (ja) * 2011-10-04 2014-11-20 コヨーテ ファーマシューティカルズ インコーポレイテッド ゲラニルゲラニルアセトン誘導体
US20140350107A1 (en) * 2011-11-09 2014-11-27 Cornell University Use of Pan-PPAR Agonists for Prevention and Treatment of Huntington's Disease and Tauopathies

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WO2008098001A2 (fr) 2007-02-05 2008-08-14 Synapse Biomedical, Inc. Électrode intramusculaire amovible
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US20110190356A1 (en) 2008-08-19 2011-08-04 Knopp Neurosciences Inc. Compositions and Methods of Using (R)- Pramipexole
US20120077753A1 (en) * 2009-06-25 2012-03-29 Laxman Gangwani Jnk inhibitors for use in treating spinal muscular atrophy
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WO2013096816A1 (fr) 2011-12-22 2013-06-27 Biogen Idec Ma Inc. Synthèse améliorée de composés substitués par amine de 4,5,6,7-tétrahydrobenzothiazole
WO2014074744A1 (fr) * 2012-11-09 2014-05-15 Lasser Elliott C Compositions de milieu de contraste pour radiographie et leurs procédés d'utilisation pour traiter une inflammation et des états associés à une inflammation.
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WO2015023790A1 (fr) 2013-08-13 2015-02-19 Knopp Biosciences Llc Compositions et méthodes pour le traitement de l'urticaire chronique
US10357543B2 (en) 2015-11-16 2019-07-23 Ohio State Innovation Foundation Methods and compositions for treating disorders and diseases using Survival Motor Neuron (SMN) protein
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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007130419A3 (fr) * 2006-05-04 2008-12-11 Merck & Co Inc Inhibiteurs de l'histone desacétylase pour le traitement de la neurodégénération
JP2010523684A (ja) * 2007-04-12 2010-07-15 パラテック ファーマシューティカルズ インコーポレイテッド テトラサイクリン化合物を用いる、脊髄筋委縮症を治療するための方法
US20130131006A1 (en) * 2010-05-11 2013-05-23 Gachon University Of Industry-Academic Cooperation Foundation Method for inhibiting the induction of cell death by inhibiting the synthesis or secretion of age-albumin in cells of the mononuclear phagocyte system
US9662347B2 (en) * 2010-05-11 2017-05-30 Gachon University Of Industry-Academic Cooperation Foundation Method for inhibiting the induction of cell death by inhibiting the synthesis or secretion of age-albumin in cells of the mononuclear phagocyte system
JP2014530810A (ja) * 2011-10-04 2014-11-20 コヨーテ ファーマシューティカルズ インコーポレイテッド ゲラニルゲラニルアセトン誘導体
US20140350107A1 (en) * 2011-11-09 2014-11-27 Cornell University Use of Pan-PPAR Agonists for Prevention and Treatment of Huntington's Disease and Tauopathies
US9592212B2 (en) * 2011-11-09 2017-03-14 Cornell University Use of pan-PPAR agonists for treatment of tauopathies

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US20060270742A1 (en) 2006-11-30
WO2006119295A3 (fr) 2007-03-15
WO2006119329A3 (fr) 2007-11-22
US20060286167A1 (en) 2006-12-21

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